Acetylcholine receptors can be divided into muscarinic (mAChR) and nicotinic (nAChR) subtypes in the mammalian central nervous system (CNS). These subtypes are distinguished based on their ability to be stimulated by either the mushroom toxin muscarine or the plant alkaloid nicotine. Nicotinic receptors are important in cholinergic transmission in autonomic ganglia, striated muscles, the neuromuscular junction, and in brain and spinal synapses.
Several types of nicotinic acetylcholine receptors (nAChRs) are known to play a role in central nervous system activity, such as, they are involved in cognition, mood and neuroprotection. The various types of known nicotinic ligands appear to have different combinations of effects on nicotine-modulated functions, depending on the subtypes of nAChRs affected, some affecting all receptors, others having more selective actions. Within the nervous system, the non-neuronal cells include microglia and astrocytes; outside the nervous system non-neuronal cells expressing alpha7 receptors include macrophages, vascular endothelium and pulmonary epithelial cells. Some nAChRs are also expressed in non-neuronal or muscle cells.
All known mammalian nAChRs are cation selective ligand-gated ion channels that form pentameric structures in the plasma membrane. Each subunit of the pentamer contains four transmembrane domains. There are at least seventeen different nAChR subunit genes, including five found in striated muscle (α1, β1, γ, δ, ε) and twelve neuronal nAChR subunits (α2-10, β2-4). These channels can be composed of a number of different combinations of subunits.
Neuronal nAChR deficits have been implicated in several diseases including AD and schizophrenia. Until recently, the study of neurodegenerative diseases focused on the muscarinic type neuronal acetylcholine receptor (mAChR) because of its abundance in the brain when compared to the population of neuronal nicotinic receptors (nAChRs). However, the discovery of a greater relative loss of nicotinic receptors than of muscarinic receptors in the Alzheimer's brain, as well as evidence that nicotinic agonists enhance cognition has spurred interest in nAChRs. This is supported by the observation of enhanced attentiveness and rapid information processing in humans receiving nicotine or 3-(2,4-dimethoxy benzylidene)-anabaseine (DMXBA) (GTS-21) treatment. The two major brain nAChRs α4β2 (“alpha4beta2”) and α7 (“alpha7”) are important for cognitive processes such as attention, learning and memory. Since brain alpha7 nicotinic receptors are spared relative to the α4β2 nAChRs in Alzheimer's disease and also possess exceptionally high calcium ion permeability, they are considered a particularly promising therapeutic target for treatment of Alzheimer's disease. In addition to their direct involvement in synaptic transmission, certain nicotinic receptor subtypes, particularly alpha7, because of their very high calcium permeability also stimulate calcium-dependent intracellular signal transduction processes that are neuroprotective by maintaining neuronal integrity in the presence of stressful states such as ischemia or mechanical trauma.
Central cholinergic neurons have been implicated in a number of neurodegenerative conditions including, Alzheimer's disease (AD) and schizophrenia. Alzheimer's disease (AD) affects an estimated 15 million people worldwide and accounts for approximately 50-60% of the overall cases of dementia for people over the age of 65. The characteristic pathology of AD includes extracellular β-amyloid plaques, intracellular neurofibrillary tangles, loss of neuronal synapes and pyramidal cells. The cholinergic dysfunction in AD is represented by a reduction in the activity of the ACh-synthesizing enzyme cholineactyltransferase (ChAT) and a loss in functional nAChRs. The cause(s) of this loss in cholinergic function is not yet known.
In schizophrenia, there is a disruption in the normal brain neuronal circuits that are responsible for filtering out responses to repetitive stimuli. This malfunction causes an overload of stimuli, which may lead to misperceptions of environmental stimuli in the form of delusions and hallucinations or withdrawal from environmental stimuli, causing schizoid behavior.
Small molecule compounds, for example, certain 3-arylidene-anabaseines, have been prepared (see, e.g., WO 2004/019943) for potential use in treating neurodegenerative diseases, and particularly with the hope that some compounds would bind to nicotinic α7 receptors. While many of the arylidene-anabaseines do selectively activate α7 receptors, these compounds also bind to other nicotinic receptors. For example, these arylidene-anabaseines also have antagonistic effects on brain α4β2 subtype nicotinic receptors, which also participate in cognitive processes, and to a lesser extent other nicotinic receptor subtypes.
The importance of developing highly selective α7 nicotinic receptor agonists has increased as the role of these receptors in degenerative disease becomes clearer. There is a particular need for new compounds useful in treating cognitive dysfunctions (such as AD and schizophrenia) where degenerative processes drastically interfere with cognitive and physiological processes.
Therefore, there is a need for development of selective α7 agonists that do not bind to and interfere with the normal functioning of other nAChRs. Such agonists would produce fewer side effects arising from interaction with other nicotinic receptor subtypes.